Protein phosphorylation is crucial in DMA repair and checkpoint controls. Our recent findings indicate that BRCT domains recognize phosphorylated peptides and associate with DNA repair proteins in a phosphorylation-dependent manner. I hypothesized that naturally found missense mutations in the BRCA1 BRCT domain may affect the normal function of BRCA1 by altering its association with phospho- proteins in breast cancer cells. This proposal aims to systematically examine the potential disruption of phospho-depenent interaction and BRCA1 function in cancer cells. This study will help us to gain insight into the molecular mechanism underlying BRCA1-mediated tumorigenesis and the development of preventive and therapeutics approaches. The overall objective of this proposal is to examine how mutations in the BRCA1 BRCT domain may affect BRCA1 function and its interaction with phosphoproteins. The specific aims of this proposal are: Aim 1: To determine the effect of cancer-associated mutations of BRCA1-BRCT domains on BRCA1 function in vivo. Aim 2: To determine the effect of cancer-associated mutations on phosphopetide binding activities of BRCA1-BRCT domains.